POS0241 MONOCYTE-DERIVED TRANSCRIPTOMES EXPLAIN THE INEFFECTIVENESS OF ABATACEPT IN RHEUMATOID ARTHRITIS
Authors: T. Iwasaki, R. Watanabe, H. Ito, T. Fujii, K. Ohmura, H. Yoshitomi, K. Murata, K. Murakami, A. Onishi, M. Tanaka, S. Matsuda, F. Matsuda, A. Morinobu, M. Hashimoto
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The factors contributing to the efficacy of abatacept in patients with rheumatoid arthritis (RA) remain unknown. <h3>Objectives</h3> We aimed to identify cellular, transcriptomic, and proteomic features that predict responses or resistance to abatacept. <h3>Methods</h3> Blood samples were collected from 22 RA patients treated with abatacept at the initiation and after three months of treatment. Response to treatment was defined based on the EULAR response criteria, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels in peripheral blood mononuclear cells (PBMCs) by RNA-Seq, 67 plasma protein levels by multiplexed immunoassay, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry, in addition to collecting clinical characteristics. Additionally, three gene expression data sets concerning the efficacy of abatacept<sup>[1–3]</sup>, comprising 37 responders and 50 non-responders in total, were used to replicate the current study. We compared the gene expression of responders versus non-responders in each set and meta-analyzed the results. <h3>Results</h3> Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment (<i>p</i> = 0.01). Regarding the transcriptome data, we found 952 differentially expressed genes (DEGs) between the responders and the non-responders before treatment initiation. A cell-type enrichment analysis showed that the DEGs were enriched in monocytes (<i>p</i> = 8.7 × 10<sup>-212</sup>, Figure 1A). Additionally, gene set enrichment analysis showed enrichment in the gene module, including <i>MYD88</i> and <i>TIRAP</i>, with the strongest significance among all of the pathways tested. When we estimated the expression of <i>MYD88</i> and <i>TIRAP</i> in monocytes by deconvolution analysis, the non-responders had higher expression before treatment initiation (<i>p</i> = 0.04 and 0.03, respectively). Among the 67 protein levels, two exhibited a correlation with the expression of the module (<i>p</i> &lt; 0.05). Of these, hepatocyte growth factor (HGF), which is produced by monocytes, was present at significantly higher concentrations in non-responders before treatment (<i>p</i> = 0.02). The analysis of the replication sets identified 1,695 DEGs. These were also enriched for the genes expressed in monocytes (<i>p</i> = 2.9 × 10<sup>-90</sup>, Figure 1B) but not for the module detected in the current study. Among the DEGs, those expressed in monocytes were enriched for the genes involved in the aerobic electron transport system in mitochondria based on gene set enrichment analysis. <h3>Conclusion</h3> Monocyte-derived transcriptomic features before treatment underlay the differences in abatacept efficacy. The pathway activated in monocytes was the <i>MYD88</i>/<i>TIRAP</i>-HGF axis in the current study, but that pathway in the replication set was the aerobic electron transport system. Overall, our results highlight the contribution of monocytes as the cells responsible for abatacept-treatment resistance and the heterogeneity of activated pathways within them. <h3>References</h3> [1]Nakamura, S. et al. Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study. Arthritis Res. Ther. 18, (2016). [2]Triaille, C. et al. Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. Front. Immunol. 12, (2021). [3]Derambure, C. et al. Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis. Arthritis Res. Ther. 19, (2017). <h3>Acknowledgements</h3> This study received funding from Astellas Pharma Inc. <h3>Disclosure of Interests</h3> Takeshi Iwasaki: None declared, Ryu Watanabe Speakers bureau: Asahi Kasei, Chugai, Eli Lilly, GSK, and Sanofi, Grant/research support from: AbbVie, Hiromu Ito Grant/research support from: Bristol Myers, Takayuki Fujii Speakers bureau: Asahi Kasei Pharma, Abbvie, Jansen, Tanabe Mitsubishi Pharma, and Eisai Co LTD, Koichiro Ohmura: None declared, Hiroyuki Yoshitomi: None declared, Koichi Murata Speakers bureau: AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp., Grant/research support from: Daiichi Sankyo Co. Ltd, Kosaku Murakami Speakers bureau: Bristol Myers, Ono Pharmaceutical, Akira Onishi Speakers bureau: Pfizer Inc., Bristol-Myers Squibb., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Grant/research support from: Pfizer Inc., Bristol-Myers Squibb., Advantest, Ayumi, and the Health Care Science Institute., Employee of: Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by grants from Daiichi Sankyo Co. Ltd. Above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, and manuscript submission., Masao Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Tanabe Mitsubishi Pharma Corp., UCB Japan Co., Ltd.., Grant/research support from: AbbVie GK, Eisai Co., Ltd., Kyowa Kirin Co., Ltd. Taisho Pharmaceutical Co., Ltd. Teijin Pharma, Ltd.., Employee of: M.T. belongs to the department financially supported by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Tanabe Mitsubishi Pharma Corp., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp. and UCB Japan Co., Ltd.)., Shuichi Matsuda: None declared, Fumihiko Matsuda: None declared, Akio Morinobu Speakers bureau: AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan., Grant/research support from: AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co. Taisho Pharmaceutical Co., Ltd.,and Eisai Co. Ltd. outside the work., Motomu Hashimoto Speakers bureau: Eli Lilly, Chugai, Mitsubishi Tanabe, Bristol Myers, Eisai, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Bristol Myers, Eisai, Daiichi Sankyo, Eli Lilly, Novartis.